Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2007) 13 P284

SFEBES2007 Poster Presentations Steroids (26 abstracts)

Identification of novel modulators of glucocorticoid sensitivity

Andrew Berry 1 , David Ray 2 & Rachelle Donn 1


1ARC Unit, Division of Epidemiology and Health Sciences, University of Manchester, Manchester, United Kingdom; 2Division of Cardiovascular and Endocrine Sciences, University of Manchester, Manchester, United Kingdom.


Glucocorticoids (GCs) are potent anti-inflammatory agents, but a variable therapeutic response occurs. We have used microarray analysis to explore the basis for inter-individual differences in the GC sensitivity of a healthy volunteer population, and identified genes predictive of response to GCs. Three such discriminating genes were then selected to be investigated for their potential to interact with the Glucocorticoid Receptor (GR). These are the Bone Morphogenetic Protein Receptor-II (BMPR-II), Interferon Inducible Protein-16 (IFI-16), and Amyloid Precursor Protein (Fe65).

To evaluate the role of BMPRII, IFI-16 and Fe65 in modulating glucocorticoid action, a cell line model was developed in HeLa cells expressing the GC responsive reporter gene, TAT3-Luciferase. The system was validated using known GR modulator proteins capable of potentiating (SRC-2), or inhibiting (NFkB) its action. The three selected genes were then evaluated in the system. Specificity was ensured by showing that neither a mutant reporter (lacking GR binding sites) or a non GR target gene (C/EBPβ) were affected.

Over-expression of BMPR-II and IFI-16 significantly increases GR transactivation of TAT3 -Luc. In contrast, the overexpression of Fe65 has no effect. Interestingly BMPR-II and IFI-16 demonstrate different sensitivities to GC treatment, since a significant effect of IFI-16 is observed using 10 nM dose of Dexamethasone (Dex), whereas cells which overexpress BMPR-II only require 1 nM Dex to elicit a significant response. Similar results were also obtained on a stably integrated TAT3 reporter.

We have used a transcriptome mapping approach to find novel GC sensitivity genes, and have validated these in a tractable, in-vitro model. This is the first time that BMPR II and IFI16 have been shown to be capable of influencing GC signalling. The mechanisms of this activity have yet to be elucidated. Such findings have potential implications for the understanding and modulation of GC sensitivity.

Article tools

My recent searches

No recent searches.